title: JunB and c-Rel cooperatively enhance Foxp3 expression during induced regulatory T cell differentiation.
abstract: The function and differentiation of induced regulatory T (iTreg) cells are tightly regulated by various signaling cascade. In this study, we have investigated the role of TCR signaling to induce Foxp3 gene expression in cooperation with TGF-β/IL-2 stimulation. Activation of CD4(+) T cells by TCR signaling or TGF-β/IL-2 alone failed to enhance Foxp3 expression. Only when TCR stimulation is coupled together with TGF-β/IL-2, CD4(+) T cells expressed high levels of Foxp3 by maintaining open chromatin structure around its promoter region. Under this condition, stimulation-dependent recruitment of JunB together with c-Rel enhanced Foxp3 expression. Over expression of JunB and c-Rel significantly enhanced Foxp3 promoter activity while treatment of JunB siRNA or inhibition of TCR signaling by MAPK inhibitors significantly reduced Foxp3 expression. Collectively our results suggest that TCR signaling together with TGF-β/IL-2 stimulation cooperatively enhance Foxp3 gene expression by maintaining accessible chromatin structure and by actively recruiting key transcription factors JunB and c-Rel.
authors.affiliation: School of Life Sciences and Immune Synapse Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
authors.forename: Jun-Seock
authors.initials: JS
authors.lastname: Son
authors.forename: Anupama
authors.initials: A
authors.lastname: Sahoo
authors.forename: Chang-Suk
authors.initials: CS
authors.lastname: Chae
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Hwang
authors.forename: Zee Yong
authors.initials: ZY
authors.lastname: Park
authors.forename: Sin-Hyeog
authors.initials: SH
authors.lastname: Im
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002843:Chromatin / Q000378:metabolism / Q000648:ultrastructure; D057890:Epigenomics; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005786:Gene Expression Regulation; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D002843:Chromatin; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D016755:Proto-Oncogene Proteins c-jun; D020569:Proto-Oncogene Proteins c-rel; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta